Cerebellar Volumetry in Ataxias: Relation to Ataxia Severity and Duration.

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

Cerebellar volumetry in ataxias: Relation to ataxia severity and duration.

Background: Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Methods: Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Results: Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Conclusion: Our results (i) confirmed SCA6 being considered as a pure cerebellar gray matter disease, (ii) emphasise the involvement of cerebellar white matter in the neurophatology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

T cell intrinsic STAT1 signaling prevents aberrant Th1 responses during acute toxoplasmosis.

Infection-induced T cell responses must be properly tempered and terminated to prevent immuno-pathology. Using transgenic mice, we demonstrate that T cell intrinsic STAT1 signaling is required to curb inflammation during acute infection with Toxoplasma gondii. Specifically, we report that mice lacking STAT1 selectively in T cells expel parasites but ultimately succumb to lethal immuno-pathology characterized by aberrant Th1-type responses with reduced IL-10 and increased IL-13 production. We also find that, unlike STAT1, STAT3 is not required for induction of IL-10 or suppression of IL-13 during acute toxoplasmosis. Each of these findings was confirmed in vitro and ChIP-seq data mining showed that STAT1 and STAT3 co-localize at the Il10 locus, as well as loci encoding other transcription factors that regulate IL-10 production, most notably Maf and Irf4. These data advance basic understanding of how infection-induced T cell responses are managed to prevent immuno-pathology and provide specific insights on the anti-inflammatory properties of STAT1, highlighting its role in shaping the character of Th1-type responses.

Quantifying MR head motion in the Rhineland Study - A robust method for population cohorts.

Head motion during MR acquisition reduces image quality and has been shown to bias neuromorphometric analysis. The quantification of head motion, therefore, has both neuroscientific as well as clinical applications, for example, to control for motion in statistical analyses of brain morphology, or as a variable of interest in neurological studies. The accuracy of markerless optical head tracking, however, is largely unexplored. Furthermore, no quantitative analysis of head motion in a general, mostly healthy population cohort exists thus far. In this work, we present a robust registration method for the alignment of depth camera data that sensitively estimates even small head movements of compliant participants. Our method outperforms the vendor-supplied method in three validation experiments: 1. similarity to fMRI motion traces as a low-frequency reference, 2. recovery of the independently acquired breathing signal as a high-frequency reference, and 3. correlation with image-based quality metrics in structural T1-weighted MRI. In addition to the core algorithm, we establish an analysis pipeline that computes average motion scores per time interval or per sequence for inclusion in downstream analyses. We apply the pipeline in the Rhineland Study, a large population cohort study, where we replicate age and body mass index (BMI) as motion correlates and show that head motion significantly increases over the duration of the scan session. We observe weak, yet significant interactions between this within-session increase and age, BMI, and sex. High correlations between fMRI and camera-based motion scores of proceeding sequences further suggest that fMRI motion estimates can be used as a surrogate score in the absence of better measures to control for motion in statistical analyses.

CerebNet: A fast and reliable deep-learning pipeline for detailed cerebellum sub-segmentation.

Quantifying the volume of the cerebellum and its lobes is of profound interest in various neurodegenerative and acquired diseases. Especially for the most common spinocerebellar ataxias (SCA), for which the first antisense oligonculeotide-base gene silencing trial has recently started, there is an urgent need for quantitative, sensitive imaging markers at pre-symptomatic stages for stratification and treatment assessment. This work introduces CerebNet, a fully automated, extensively validated, deep learning method for the lobular segmentation of the cerebellum, including the separation of gray and white matter. For training, validation, and testing, T1-weighted images from 30 participants were manually annotated into cerebellar lobules and vermal sub-segments, as well as cerebellar white matter. CerebNet combines FastSurferCNN, a UNet-based 2.5D segmentation network, with extensive data augmentation, e.g. realistic non-linear deformations to increase the anatomical variety, eliminating additional preprocessing steps, such as spatial normalization or bias field correction. CerebNet demonstrates a high accuracy (on average 0.87 Dice and 1.742mm Robust Hausdorff Distance across all structures) outperforming state-of-the-art approaches. Furthermore, it shows high test-retest reliability (average ICC >0.97 on OASIS and Kirby) as well as high sensitivity to disease effects, including the pre-ataxic stage of spinocerebellar ataxia type 3 (SCA3). CerebNet is compatible with FreeSurfer and FastSurfer and can analyze a 3D volume within seconds on a consumer GPU in an end-to-end fashion, thus providing an efficient and validated solution for assessing cerebellum sub-structure volumes. We make CerebNet available as source-code (https://github.com/Deep-MI/FastSurfer).

Characteristics and Demographics of Patients Requiring Emergent Air Medical.

Background: As integrated health systems become more common, interfacility patient transfers will increase and air transport programs will be prioritized. Understanding characteristics of patients triaged to air medical transport will assist with resource allocation and needs assessment. The objective of this study was to investigate the demographics and clinical characteristics of patients that presented to the emergency department (ED) and subsequently required emergent air medical interfacility transport. Methods: This was a retrospective, multicenter study conducted at eight hospitals within Northwell Health, the largest academic health system in New York state. The study was conducted between December 1, 2014, and July 31, 2020, and included patients who presented to an ED and subsequently required emergent air medical interfacility transport. Results: Overall, the median age was 37 years (IQR 4-66), and 231 (54%) subjects were males. The majority of subjects (59%) had no reported comorbidities, arrived by ambulance (52%), and were emergency severity index triage 2 (48%). Frequent indications for transfer were nontraumatic neurologic (37%), pulmonary or respiratory (13%), trauma (12%), and cardiovascular (12%). Most patients were not ventilated before transport (71%). The median time to call for transport at the sending institution was 2:42 hours (IQR 1:14-6:54), and the median length of stay was 4:12 (IQR 2:31-8:48). Most patients were subsequently admitted (96%) at the receiving institution to an intensive care unit (72%). Conclusions: This study describes patients' demographic and clinical characteristics who required emergent air medical transport. Helicopter transport is costly, and data from these patients may further help our understanding of who is transported by air and how important air transport is to the health system.

FastSurferVINN: Building resolution-independence into deep learning segmentation methods-A solution for HighRes brain MRI.

Leading neuroimaging studies have pushed 3T MRI acquisition resolutions below 1.0 mm for improved structure definition and morphometry. Yet, only few, time-intensive automated image analysis pipelines have been validated for high-resolution (HiRes) settings. Efficient deep learning approaches, on the other hand, rarely support more than one fixed resolution (usually 1.0 mm). Furthermore, the lack of a standard submillimeter resolution as well as limited availability of diverse HiRes data with sufficient coverage of scanner, age, diseases, or genetic variance poses additional, unsolved challenges for training HiRes networks. Incorporating resolution-independence into deep learning-based segmentation, i.e., the ability to segment images at their native resolution across a range of different voxel sizes, promises to overcome these challenges, yet no such approach currently exists. We now fill this gap by introducing a Voxel-size Independent Neural Network (VINN) for resolution-independent segmentation tasks and present FastSurferVINN, which (i) establishes and implements resolution-independence for deep learning as the first method simultaneously supporting 0.7-1.0 mm whole brain segmentation, (ii) significantly outperforms state-of-the-art methods across resolutions, and (iii) mitigates the data imbalance problem present in HiRes datasets. Overall, internal resolution-independence mutually benefits both HiRes and 1.0 mm MRI segmentation. With our rigorously validated FastSurferVINN we distribute a rapid tool for morphometric neuroimage analysis. The VINN architecture, furthermore, represents an efficient resolution-independent segmentation method for wider application.

Expamers: a new technology to control T cell activation.

T cell activation is a cornerstone in manufacturing of T cell-based therapies, and precise control over T cell activation is important in the development of the next generation T-cell based therapeutics. This need cannot be fulfilled by currently available methods for T cell stimulation, in particular not in a time dependent manner. Here, we describe a modular activation reagent called Expamers, which addresses these limitations. Expamers are versatile stimuli that are intended for research and clinical use. They are readily soluble and can be rapidly bound and removed from the cell surface, allowing nearly instantaneous initiation and termination of activation signal, respectively. Hence, Expamers enable precise regulation of T cell stimulation duration and provide promise of control over T cell profiles in future products. Expamers can be easily adopted to different T cell production formats and have the potential to increase efficacy of T cell immunotherapeutics.

i3PosNet: instrument pose estimation from X-ray in temporal bone surgery.

PURPOSE: Accurate estimation of the position and orientation (pose) of surgical instruments is crucial for delicate minimally invasive temporal bone surgery. Current techniques lack in accuracy and/or line-of-sight constraints (conventional tracking systems) or expose the patient to prohibitive ionizing radiation (intra-operative CT). A possible solution is to capture the instrument with a c-arm at irregular intervals and recover the pose from the image. METHODS: i3PosNet infers the position and orientation of instruments from images using a pose estimation network. Said framework considers localized patches and outputs pseudo-landmarks. The pose is reconstructed from pseudo-landmarks by geometric considerations. RESULTS: We show i3PosNet reaches errors [Formula: see text] mm. It outperforms conventional image registration-based approaches reducing average and maximum errors by at least two thirds. i3PosNet trained on synthetic images generalizes to real X-rays without any further adaptation. CONCLUSION: The translation of deep learning-based methods to surgical applications is difficult, because large representative datasets for training and testing are not available. This work empirically shows sub-millimeter pose estimation trained solely based on synthetic training data.

Leveraging spatial uncertainty for online error compensation in EMT.

PURPOSE: Electromagnetic tracking (EMT) can potentially complement fluoroscopic navigation, reducing radiation exposure in a hybrid setting. Due to the susceptibility to external distortions, systematic error in EMT needs to be compensated algorithmically. Compensation algorithms for EMT in guidewire procedures are only practical in an online setting. METHODS: We collect positional data and train a symmetric artificial neural network (ANN) architecture for compensating navigation error. The results are evaluated in both online and offline scenarios and are compared to polynomial fits. We assess spatial uncertainty of the compensation proposed by the ANN. Simulations based on real data show how this uncertainty measure can be utilized to improve accuracy and limit radiation exposure in hybrid navigation. RESULTS: ANNs compensate unseen distortions by more than 70%, outperforming polynomial regression. Working on known distortions, ANNs outperform polynomials as well. We empirically demonstrate a linear relationship between tracking accuracy and model uncertainty. The effectiveness of hybrid tracking is shown in a simulation experiment. CONCLUSION: ANNs are suitable for EMT error compensation and can generalize across unseen distortions. Model uncertainty needs to be assessed when spatial error compensation algorithms are developed, so that training data collection can be optimized. Finally, we find that error compensation in EMT reduces the need for X-ray images in hybrid navigation.

Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T cell Function against Multiple Myeloma Is Enhanced in the Presence of Lenalidomide.

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells have shown promising clinical responses in patients with relapsed/refractory multiple myeloma. Lenalidomide, an immunomodulatory drug, potentiates T cell functionality, drives antimyeloma activity, and alters the suppressive microenvironment; these properties may effectively combine with anti-BCMA CAR T cells to enhance function. Using an anti-BCMA CAR T, we demonstrated that lenalidomide enhances CAR T cell function in a concentration-dependent manner. Lenalidomide increased CAR T effector cytokine production, particularly under low CAR stimulation or in the presence of inhibitory ligand programmed cell death 1 ligand 1. Notably, lenalidomide also enhanced CAR T cytokine production, cytolytic activity, and activation profile relative to untreated CAR T cells in chronic stimulation assays. This unique potentiation of both short-term CAR T activity and long-term functionality during chronic stimulation prompted investigation of the molecular profile of lenalidomide-treated CAR T cells. Signatures from RNA sequencing and assay for transposase-accessible chromatin using sequencing indicated that pathways associated with T-helper 1 response, cytokine production, T cell activation, cell-cycle control, and cytoskeletal remodeling were altered with lenalidomide. Finally, study of lenalidomide and anti-BCMA CAR T cells in a murine, disseminated, multiple myeloma model indicated that lenalidomide increased CAR T cell counts in blood and significantly prolonged animal survival. In summary, preclinical studies demonstrated that lenalidomide potentiated CAR T activity in vivo in low-antigen or suppressive environments and delayed onset of functional exhaustion. These results support further investigation of lenalidomide and anti-BCMA CAR T cells in the clinic.

High-precision evaluation of electromagnetic tracking.

PURPOSE: Navigation in high-precision minimally invasive surgery (HP-MIS) demands high tracking accuracy in the absence of line of sight (LOS). Currently, no tracking technology can satisfy this requirement. Electromagnetic tracking (EMT) is the best tracking paradigm in the absence of LOS despite limited accuracy and robustness. Novel evaluation protocols are needed to ensure high-precision and robust EMT for navigation in HP-MIS. METHODS: We introduce a novel protocol for EMT measurement evaluation featuring a high-accuracy phantom based on LEGO[Formula: see text], which is calibrated by a coordinate measuring machine to ensure accuracy. Our protocol includes relative sequential positions and an uncertainty estimation of positioning. We show effects on distortion compensation using a learned interpolation model. RESULTS: Our high-precision protocol clarifies properties of errors and uncertainties of EMT for high-precision use cases. For EMT errors reaching clinically relevant 0.2 mm, our design is 5-10 times more accurate than previous protocols with 95% confidence margins of 0.02 mm. This high-precision protocol ensures the performance improvement in compensated EMT by 0.05 mm. CONCLUSION: Our protocol improves the reliability of EMT evaluations because of significantly lower protocol-inherent uncertainties. To reduce patient risk in HP-MIS and to evaluate magnetic field distortion compensation, more high-accuracy protocols such as the one proposed here are required.

Systemic toxoplasma infection triggers a long-term defect in the generation and function of naive T lymphocytes.

Because antigen-stimulated naive T cells either die as effectors or enter the activated/memory pool, continuous egress of new T lymphocytes from thymus is essential for maintenance of peripheral immune homeostasis. Unexpectedly, we found that systemic infection with the protozoan Toxoplasma gondii triggers not only a transient increase in activated CD4+ Th1 cells but also a persistent decrease in the size of the naive CD4+ T lymphocyte pool. This immune defect is associated with decreased thymic output and parasite-induced destruction of the thymic epithelium, as well as disruption of the overall architecture of that primary lymphoid organ. Importantly, the resulting quantitative and qualitative deficiency in naive CD4+ T cells leads to an immunocompromised state that both promotes chronic toxoplasma infection and leads to decreased resistance to challenge with an unrelated pathogen. These findings reveal that systemic infectious agents, such as T. gondii, can induce long-term immune alterations associated with impaired thymic function. When accumulated during the lifetime of the host, such events, even when occurring at low magnitude, could be a contributing factor in immunological senescence.

ß8 Integrin Expression and Activation of TGF-ß by Intestinal Dendritic Cells Are Determined by Both Tissue Microenvironment and Cell Lineage.

Activation of TGF-ß by dendritic cells (DCs) expressing αvß8 integrin is essential for the generation of intestinal regulatory T cells (Tregs) that in turn promote tolerance to intestinal Ags. We have recently shown that αvß8 integrin is preferentially expressed by CD103(+) DCs and confers their ability to activate TGF-ß and generate Tregs. However, how these DCs become specialized for this vital function is unknown. In this study, we show that ß8 expression is controlled by a combination of factors that include DC lineage and signals derived from the tissue microenvironment and microbiota. Specifically, our data demonstrate that TGF-ß itself, along with retinoic acid and TLR signaling, drives expression of αvß8 in DCs. However, these signals only result in high levels of ß8 expression in cells of the cDC1 lineage, CD8α(+), or CD103(+)CD11b(-) DCs, and this is associated with epigenetic changes in the Itgb8 locus. Together, these data provide a key illustrative example of how microenvironmental factors and cell lineage drive the generation of regulatory αvß8-expressing DCs specialized for activation of TGF-ß to facilitate Treg generation.

Inflammatory Th17 Cells Express Integrin αvß3 for Pathogenic Function.

Interleukin-23 (IL-23) is required for inflammatory Th17 cell function in experimental autoimmune encephalomyelitis (EAE), and IL-23 blockade reduces the number of effector Th17 cells in the CNS. We report that pro-inflammatory Th17 cells express high integrin ß3 that is IL-23 dependent. Integrin ß3 was not upregulated on all activated T cells; rather, integrin ß3 was upregulated along with its functional partner integrin αv on effector Th17 cells and "ex-Th17" cells, and αvß3(hi) RORγt(+) cells expanded during EAE. Integrin αvß3 inhibitors ameliorated clinical signs of EAE, and integrin ß3 deficiency on CD4(+) T cells alone was sufficient to block EAE induction. Furthermore, integrin-ß3-deficient Th17 cells, but not Th1 cells, were impaired in their ability to induce EAE. Integrin ß3(-/-) T cells induced smaller demyelinated lesions and showed reduced spread and accumulation within the CNS, corresponding with impaired extracellular-matrix-mediated migration. Hence, integrin ß3 is required for Th17 cell-mediated autoimmune CNS inflammation.

miR-155 activates cytokine gene expression in Th17 cells by regulating the DNA-binding protein Jarid2 to relieve polycomb-mediated repression.

Specification of the T helper 17 (Th17) cell lineage requires a well-defined set of transcription factors, but how these integrate with posttranscriptional and epigenetic programs to regulate gene expression is poorly understood. Here we found defective Th17 cell cytokine expression in miR-155-deficient CD4+ T cells in vitro and in vivo. Mir155 was bound by Th17 cell transcription factors and was highly expressed during Th17 cell differentiation. miR-155-deficient Th17 and T regulatory (Treg) cells expressed increased amounts of Jarid2, a DNA-binding protein that recruits the Polycomb Repressive Complex 2 (PRC2) to chromatin. PRC2 binding to chromatin and H3K27 histone methylation was increased in miR-155-deficient cells, coinciding with failure to express Il22, Il10, Il9, and Atf3. Defects in Th17 cell cytokine expression and Treg cell homeostasis in the absence of Mir155 could be partially suppressed by Jarid2 deletion. Thus, miR-155 contributes to Th17 cell function by suppressing the inhibitory effects of Jarid2.

CD4+ T cells are trigger and target of the glucocorticoid response that prevents lethal immunopathology in toxoplasma infection.

Synthetic glucocorticoids (GCs) are commonly used in the treatment of inflammatory diseases, but the role of endogenous GCs in the regulation of host-protective immune responses is poorly understood. Here we show that GCs are induced during acute Toxoplasma gondii infection and directly control the T cell response to the parasite. When infected with toxoplasma, mice that selectively lack GC receptor (GR) expression in T cells (GR(lck-Cre)) rapidly succumb to infection despite displaying parasite burdens indistinguishable from control animals and unaltered levels of the innate cytokines IL-12 and IL-27. Mortality in the GR(lck-Cre) mice was associated with immunopathology and hyperactive Th1 cell function as revealed by enhanced IFN-γ and TNF production in vivo. Unexpectedly, these CD4(+) T lymphocytes also overexpressed IL-10. Importantly, CD4(+) T cell depletion in wild-type or GR(lck-Cre) mice led to ablation of the GC response to infection. Moreover, in toxoplasma-infected RAG(-/-) animals, adoptive transfer of CD4(+) T lymphocytes was required for GC induction. These findings establish a novel IL-10-independent immunomodulatory circuit in which CD4(+) T cells trigger a GC response that in turn dampens their own effector function. In the case of T. gondii infection, this self-regulatory pathway is critical for preventing collateral tissue damage and promoting host survival.

Caspase-1 independent IL-1beta production is critical for host resistance to mycobacterium tuberculosis and does not require TLR signaling in vivo.

To investigate the respective contributions of TLR versus IL-1R mediated signals in MyD88 dependent control of Mycobacterium tuberculosis, we compared the outcome of M. tuberculosis infection in MyD88, TRIF/MyD88, IL-1R1, and IL-1beta-deficient mice. All four strains displayed acute mortality with highly increased pulmonary bacterial burden suggesting a major role for IL-1beta signaling in determining the MyD88 dependent phenotype. Unexpectedly, the infected MyD88 and TRIF/MyD88-deficient mice, rather than being defective in IL-1beta expression, displayed increased cytokine levels relative to wild-type animals. Similarly, infected mice deficient in caspase-1 and ASC, which have critical functions in inflammasome-mediated IL-1beta maturation, showed unimpaired IL-1beta production and importantly, were considerably less susceptible to infection than IL-1beta deficient mice. Together our findings reveal a major role for IL-1beta in host resistance to M. tuberculosis and indicate that during this infection the cytokine can be generated by a mechanism that does not require TLR signaling or caspase-1.

Eating disorder behaviors and depression: a minimal relationship beyond social comparison, self-esteem, and body dissatisfaction.

Existing literature fails to comprehensively identify factors contributing to the comorbid relationship between eating disorder (ED) behaviors and unipolar depression. Maladaptive social comparison, body dissatisfaction, and low self-esteem are disruptive psychological patterns common to both constructs. It is unclear whether a unique relationship exists between depression and eating disorder behaviors beyond the effects exerted by this negative cognitive triad. The purpose of the present study is to examine whether a unique relationship exists between depression and ED behaviors after controlling for maladaptive social comparison, body dissatisfaction, and low self-esteem. We predict minimal unique variance in ED behaviors will be explained by depression after controlling for this negative cognitive triad.